Methylmercury (MeHg) is a well-recognized neurotoxic agent that can affect the fetus. In the tragic disasters that took place at Minamata, Japan, and subsequently in Iraq, many infants were exposed transplacentally to MeHg. The victims manifested a cerebral palsy-like syndrome characterized by severe mental retardation, motor dysfunction, and repeated convulsions. Histological examination revealed widespread neuronal degeneration, abnormal arrangement of neurons in the cerebrum and cerebellum, and diffuse white matter gliosis in the brain of victims. Even now, MeHg is a major environmental problem, since it accumulates in the aquatic food chain and consequently creates a risk to the human brain, especially that of the fetus. The long-term goal of the present proposal is to elucidate the cellular and molecular mechanisms underlying MeHg-induced malformation of the brain. We will focus on the effects of MeHg on neuronal cell migration in the developing brain since it has been suggested that MeHg can disturb the process of neuronal cell migration. To this end, we will use the cerebellum as a model system because the effect of methylmercury on brain growth is marked in the cerebellum. We will determine the effects of MeHg on the migration of cerebellar neurons. First, we will determine how MeHg administration affects the migration in vivo and in vitro. Second, we will determine if MeHg alter migration by altering the Ca2+ signaling pathway. Third, we will determine if the interaction between the Ca2+, cAMP and cGMP signaling pathways synergistically alters the effects of MeHg on migration. Fourth, we will determine if the interaction between the Ca2+ signaling and the ROS production plays a crucial role in MeHg-induced impairment of migration. The fundamental mechanisms whereby MeHg administration leads to the disturbances of brain development have not been delineated definitively. Answers to the questions raised in this project will provide a new understanding as to how prenatal and early postnatal exposure to MeHg causes malformation of the brain. Lay Summary PUBLIC HEALTH RELEVANCE In the late 1950s, many infants born in Minamata of Japan developed characteristic neurological symptoms, including mental retardation and cerebral palsy. Later it has revealed that methylmercury (MeHg) induced congenital intoxication via the transplacental transfer of mercury to the fetus. The term fetal Minamata disease (FMD) was used to describe such medical phenomenon. The most characteristic symptoms of FMD are mental retardation, dysarthria, cerebellar symptoms (such as ataxia), and deformity of the limbs. Furthermore, histological studies revealed that in FMD disruption of the cerebral and cerebellar cytoarchitecture was prominent. Many neurons appeared to be hypoplastic, ectopic, dysplastic, and disoriented, strongly indicative of disrupted migration, maturation, and growth. Extensive neuronal loss occurred throughout the brain. MeHg exposure remains a major public health concern because of natural and anthropogenic release of inorganic mercury into the aquatic environment, where it is biotransformed by algae and bacteria into MeHg. This can pass along the food chain and, eventually, to man. The long-term goal of the present proposal is to reveal the cellular and molecular mechanisms underlying the MeHg-induced malformation of the brain. In particular, we focus on the study examining whether MeHg exposure impairs neuronal cell migration in the developing brain. The fundamental mechanisms whereby MeHg exposure leads to disturbances of brain development have not been delineated definitively. Answers to the questions raised in this project will provide insights for development of therapies that counter MeHg-induced brain malformation.